ABSTRACT Chronic obstructive pulmonary disease (COPD) is a major public health problem. This debilitating condition is projected to be the third most common cause of death and the fifth most common cause of disability in the world by 2020. Occupational exposure to dusts is a significant risk factor for COPD and as much as 15% of COPD cases may be attributable to occupational exposures. Farming is among the occupations associated with COPD and the prevalence of COPD among farmers has been found to be 17- 32%, even after adjustment for competing risks such as gender, age and smoking. Although it is likely that multiple components in various agricultural work environments are involved in the development of COPD, bacterial and fungal components have emerged as major factors of concern in agricultural work settings. Bacteria, fungi and their respective components are recognized and signal through the innate immune system via pathogen recognition receptors, which include the Toll-Like Receptors, the Dectin-1 cluster receptors and the NOD-Like receptors. The premise of our approach in this proposal is that with different environmental exposures, different genes may be activated and contribute to disease susceptibility. Single nucleotide polymorphisms in these receptors and their accessory molecules have been identified; however there have been no epidemiological studies examining the role of these pathogen recognition receptors in COPD. The overall working hypothesis of this study is that genetic variation in pathogen recognition receptors and their accessory molecules that interact with bacterial and fungal components alters susceptibility to COPD in an agriculturally exposed population. Furthermore, we hypothesize that functional polymorphisms in these genes can be recognized by receptor expression or ligand- receptor stimulation. We will address these hypotheses with the following specific aims: In a case-control study among agriculturally-exposed subjects, determine whether genetic variation in pathogen recognition receptors that bind Gram (+) and Gram (-) bacterial components, as well as fungal components, are associated with COPD, chronic bronchitis symptoms and/or lung function; and to determine whether there is an association of these polymorphisms with receptor expression and responses of blood mononuclear cells to stimulation with their respective ligands. Assessment of the genomics and potential novel pathways that influence COPD in veterans with agricultural exposure is understudied and a highly innovative hypothesis which could lead to advances in our overall understanding of COPD in the general population. We anticipate that this project could advance us towards the development of pharmacogenetic-based treatments for COPD and address the VA initiative towards genomic medicine. ) ) PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Agriculture is vital to the economy of the VA Midwest Health Care Network (VISN 23) and rural veterans are part of the workforce in agriculture. COPD is a frequent condition that afflicts veterans. Although cigarette smoking is clearly a risk factor for COPD, agricultural work in particular is associated with COPD. Assessment of the genomics and potential novel signaling pathways that influence COPD in veterans with agricultural exposure is understudied and an innovative hypothesis which could lead to advances in our overall understanding of COPD in the general population. This effort is the first to examine the complex association of pathogen recognition receptor genes and COPD in individuals exposed to agriculture, important given the association of COPD with disability, escalating treatment costs and heightened mortality among farmers. We anticipate that this project will contribute to more specific prevention and therapeutic strategies and address the VA initiative towards genomic medicine. )